We propose to synthesize potent, enzyme-resistant and receptor- specific opioid peptide analogs. The development of both agonists and antagonists with high specificity for the three major opioid receptor types (mu, delta, kappa) will be attempted. The analog design will primarily be based on the principle of conformational restriction through peptide cyclizations via side-chains. The compounds to be synthesized will serve a dual purpose: a) they will represent novel tools for research aimed at elucidating the molecular mechanism(s) of action of opioid compounds and at clarifying the physiological role of the various opioid receptor classes; and b) some of the peptide analogs might have potential as novel analgesics. To reach these goals we use an interdisciplinary approach based on the well-integrated application of chemical, physico-chemical, biochemical and pharmacologic methods.
Specific aims i nclude: a) synthesis of cyclic opioid peptide analogs structurally related to dermorphin and beta- casomorphin (Phe in 3-position); b) preparation of cyclic peptides related to enkephalin and metorphamide (Phe in 4-position); c) synthesis of stable dynorphin A-(1-13) analogs characterized by various peptide bond replacements in the 1-2 position and/or containing cyclic elements in the middle or C-terminal regions of the peptide chain; d) conformational studies by NMR spectroscopy and X-ray diffraction analysis; e) determination of receptor affinities and selectivities of the new compounds in binding assays based on displacement of mu-, delta- and kappa-selective radioligands from rat brain or guinea pig ileum membrane binding sites; f) evaluation of agonist or antagonist properties of the analogs in bioassays based on inhibition of electrically evoked contractions of the guinea pig ileum and of the vasa deferentia of the mouse, rat and rabbit; g) examination of the stability of the compounds against enzymatic degradation; and h) tests of the analgesic properties of the analogs in vivo using the mouse or rat tail flick test.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Clinical Research Institute of Montreal
Zip Code
H2 1R7
Gendron, Louis; Cahill, Catherine M; von Zastrow, Mark et al. (2016) Molecular Pharmacology of δ-Opioid Receptors. Pharmacol Rev 68:631-700
Tan, Paul; Blais, Carolane; Nguyen, Thi M-D et al. (2016) Prorenin/renin receptor blockade promotes a healthy fat distribution in obese mice. Obesity (Silver Spring) 24:1946-54
Weltrowska, Grazyna; Nguyen, Thi M-D; Chung, Nga N et al. (2016) A Cyclic Tetrapeptide (""Cyclodal"") and Its Mirror-Image Isomer Are Both High-Affinity μ Opioid Receptor Antagonists. J Med Chem :
Cai, Yunxin; Lu, Dandan; Chen, Zhen et al. (2016) [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1. Bioorg Med Chem Lett 26:3629-31
Guillemyn, Karel; Starnowska, Joanna; Lagard, Camille et al. (2016) Bifunctional Peptide-Based Opioid Agonist-Nociceptin Antagonist Ligands for Dual Treatment of Acute and Neuropathic Pain. J Med Chem 59:3777-92
Betti, Cecilia; Starnowska, Joanna; Mika, Joanna et al. (2015) Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics. ACS Med Chem Lett 6:1209-14
Möröy, Tarik; Vassen, Lothar; Wilkes, Brian et al. (2015) From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation. Blood 126:2561-9
Schiller, Peter W; Nguyen, Thi M-D; Saray, Amy et al. (2015) The bifunctional μ opioid agonist/antioxidant [Dmt(1)]DALDA is a superior analgesic in an animal model of complex regional pain syndrome-type i. ACS Chem Neurosci 6:1789-93
Fenalti, Gustavo; Zatsepin, Nadia A; Betti, Cecilia et al. (2015) Structural basis for bifunctional peptide recognition at human δ-opioid receptor. Nat Struct Mol Biol 22:265-8
Guillemyn, Karel; Kleczkowska, Patrycia; Lesniak, Anna et al. (2015) Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist - neurokinin-1 antagonist peptidomimetics. Eur J Med Chem 92:64-77

Showing the most recent 10 out of 98 publications